1. Field of the Invention
The present invention relates to the use of free acid S(+) flurbiprofen to elicit a sustained and enhanced antipyretic response in mammalian organisms in need of such treatment, and to certain pharmaceutical compositions comprising unit dosage effective amounts of S(+) flurbiprofen.
2. Description of the Art
Flurbiprofen, also known as (.+-.)-2-fluoro-.alpha.-methyl-[1,1'-biphenyl]-4-acetic acid, as (.+-.)-2-fluoro-.alpha.-methyl-4-biphenylacetic acid or as (.+-.)-2-(2-fluoro-4-biphenylyl)propionic acid, is described in U.S. Pat. No. 3,755,427 and has the structural formula: ##STR1## The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. Flurbiprofen is marketed in the United States for the treatment of arthritis but not as an analgesic and it has been on the market in numerous countries overseas, including Europe, for a number of years. Tradenames and codenames by which it is known include Ansaid, Cebutid, Froben, BTS 18322 and U-27182. As Froben, the drug is available abroad as tablets containing 50 or 100 mg of flurbiprofen. For rheumatic disorders such as rheumatoid arthritis, it is recommended at a daily dose of 150 to 200 mg in divided doses of two to four per day, increased to a daily dose of 300 mg in acute conditions. See Martindale, The Extra Pharmacopoeia, 28th edition, ed. James E. F. Reynolds, London, The Pharmaceutical Press, 1982, p. 255. As an analgesic, it is usually administered at the 50 mg dosage level every 4 to 6 hours, up to 300 mg per day. Flurbiprofen has been found useful in controlling acute and chronic pain, including that associated with ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, postsurgical dental pain, postsurgical gynecological pain, postpartum uterine pain, primary dysmenorrhea, cancer pain, the pain of acute gout and the pain of acute bursitis/tendinitis of the shoulder. See The American Journal of Medicine, Proceedings of a Symposium, "Control of Acute and Chronic Pain with Ansaid (Flurbiprofen)", ed. Abraham Sunshine, M. D., Volume 80 (3A), Mar. 24, 1986.
As is apparent from its chemical nomenclature, flurbiprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been a few isolated studies of the individual S(+) and R(-) isomers reported in the literature. These reflect that the S(+) enantiomer, analogously to other 2-arylpropionic acids, is the active form of flurbiprofen.
Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed the earlier work on the metabolic chiral inversion of 2-arylpropionic acids, including ibuprofen, which they indicated was the first substituted 2-arylpropionic acid conclusively shown to undergo the inversion as well as the most studied member of the group. The authors noted that early workers found no significant difference in in vivo activity among the R(-) and S(+) isomers and the racemic mixture of ibuprofen in three different animal models, but very large differences in vitro between the R(-) and S(+) isomers, ascribing this discrepancy to the virtually quantitative conversion of the R(-) to the active S(+) isomer in vivo.
In the same paper, Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive R(-) isomer was not converted in vivo to the active S(+) isomer as readily as ibuprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the S(+) enantiomer to date. Hutt et al concluded:
It is likely that benefits will be obtained from the use of the S(+)-enantiomer of 2-arylpropionates as drugs as opposed to the racemates. This is only found at present in the case of naproxen. In cases of rapid inversion, the inactive R(-) isomer serves merely as a prodrug for the active S(+)-antipode. Where inversion is slow, the R(-) enantiomer is an unnecessary impurity in the active S(+) form. Use of the S(+)-enantiomer would permit reduction of the dose given, remove variability in rate and extent of inversion as a source of variability in therapeutic response and would reduce any toxicity arising from non-stereospecific mechanisms.
Thus, in cases of rapid inversion, such as ibuprofen, where substantially equivalent in vivo responses have been reported for the individual enantiomers and the racemic drug, Hutt et al suggested that no benefits would be obtained from the use of the S(+) isomer because the inactive R(-) isomer merely acts as a prodrug for the active S(+) form. Contrariwise, in cases where chiral inversion is slow, e.g., naproxen, the use of the S(+) enantiomer is desirable for the several reasons enumerated by Hutt et al. Indeed, naproxen has been reported to be marketed as the d-isomer for one of the reasons given by Hutt et al, i.e., to reduce side effects (Allison et al, "Naproxen," Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRC Press Inc., Boca Raton, Fla., 1985, p. 172). However, the 1983 Hutt et al review is silent as to the possibility of chiral inversion in the case of flurbiprofen.
Another general report on earlier work has been provided by Hutt et al in Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on the importance of stereochemical considerations in the clinical pharmacokinetics of 2-aryl-propionic acids, the authors tabulated relative potencies of the enantiomers of a number of 2-arylpropionic acids in vivo and in vitro. The in vitro results showed the S or (+) isomer in each case to be the more active species. In vivo, however, the results were not consistent across the entire class. Thus, the results for naproxen demonstrated the S or (+) isomer to be much more active in vivo, indicating a relatively slow inversion of the inactive R or (-) isomer to the active S or (+) isomer; the results for fenoprofen and ibuprofen, on the other hand, demonstrated the inactive R or (-) and the active S or (+) isomers to be approximately equally effective in vivo, indicating a rapid inversion of R or (-) isomer to S or (+) isomer. Hutt et al indicated that flurbiprofen had an S(+)/R(-) activity ratio in vivo of 878 and in vitro 2-16; the in vitro study involved antagonism of rat SRS-A on the tracheal chain of guinea pigs and the in vivo study assessed guinea pig anaphylaxis. The reference cited by Hutt et al for the flurbiprofen studies was Greig et al, J. Med. Chem. 18, 112-116 (1975).
Greig et al, who were associated with the Upjohn Company, one of the developers of flurbiprofen, studied the antagonism of slow reacting substance in anaphylaxis (SRS-A) and other spasmogens on the guinea pig tracheal chain by hydrotropic acids. Greig et al also studied the ability of the hydrotropic acids to protect guinea pigs against anaphylaxis. Among the substances tested were racemic flurbiprofen, (+) flurbiprofen and (-) flurbiprofen.
In the in vitro testing, the (+) isomer was found to be many times more effective than the racemate; indeed, the authors found that the (-) isomer inhibited the effect of the (+) isomer in antagonism of rat SRS-A on guinea pig trachea in vitro. In the in vivo testing, Greig et al found that flurbiprofen and its isomers were active in protecting sensitized guinea pigs against anaphylactic shock when they were challenged 4 weeks after sensitization. These results correlated well with the in vitro activity. In vivo, the (+) isomer had more than a two-fold effect over the racemate; at 80% protection, the (+) isomer was 5 to 7 times more active than the racemic mixture. The (-) isomer was the least active of the three compounds.
The Greig et al studies concerned themselves with anaphylaxis and bronchospasm; as such, they have no relevancy to an antipyretic response.
Nishizawa et al, also associated with Upjohn, reported in Thrombosis Research 3, 577-588 (1973) on flurbiprofen as a potent inhibitor of platelet aggregation in animals and man. They found that the platelet anti-aggregating effect resided in the d-isomer; the 1-isomer was without anti-aggregating effect and neither counteracted nor enhanced the effect of the d-isomer. The optical antipodes were tested in rats. Anti-aggregating effects, however, do not correlate with models for analgesia or inflammation.
Kulmacz et al, J. Biol. Chem. 260, 12572-12578 (1985), studied the interaction of flurbiprofen with prostaglandin H synthase. They reported that 1.2 .+-.0.1 mol of S(+) flurbiprofen per mol of synthase dimer resulted in maximum inhibition of the cyclooxygenase enzyme. Racemic flurbiprofen required 2.4.+-.0.3 mol per mol synthase dimer for full effect, and the R(-) isomer was not inhibitory, even at a ratio of 2.5/dimer. From their own studies and those of Nishizawa et al in inhibiting rat platelet aggregation, Kulmacz et al concluded that the flurbiprofen isomers follow the pattern observed for many anti-inflammatory agents, i.e., the dextrorotatory form is usually more potent pharmacologically than the levorotatory isomer. This is borne out by the teachings of Armitage et al, U.S. Pat. No. 4,501,727, dated Feb. 26, 1985. The Armitage et al patent relates to a novel light-stable N-methyl-D-glucamine salt of the dextrorotatory or (+) isomer. It teaches that flurbiprofen has anti-inflammatory, analgesic and antipyretic properties, and that the (+) enantiomer is the pharmacologically active isomer.
In summary, the current state of the art assumes that, in mammals, analogously to other 2-arylpropionic acid NSAID's, the S(+) form is the active enantiomer of flurbiprofen. However, there do not appear to be any human or other animal experiments on efficacy of the separate enantiomers in antipyretic models reported in the literature. The prior art, moreover, is conspicuously silent in respect to any sustainedly enhanced alleviation of mammalian fever utilizing whatever form of the flurbiprofen drug species.